Signal transducer and activator of transcription (Stat)-family proteins are latent cytoplasmic transcription factors that convey signals from the cell surface to the nucleus on activation by cytokines and growth factors. See Yu and Jove, Nat Rev 4:97-105 (2004) and Levy and Darnell, Nat Rev Mol Cell Biol 3:651-662 (2002). Engagement of cell surface receptors by polypeptide ligands, such as interleukin-6 (IL-6) or epidermal growth factor, induces tyrosine phosphorylation of Stat proteins by Janus kinase, growth factor receptor tyrosine kinases, and Src family tyrosine kinases. The phosphorylated Stat protein in the activated dimeric form then translocates to the nucleus and regulates expression of genes having Stat-binding sites in their promoters. Under normal physiologic conditions, activation of Stat proteins is rapid, transient and regulates expression of genes that control fundamental biological processes, including cell proliferation, survival, and development.
Numerous studies have detected constitutively active Stat, particularly Stat1, Stat3 and Stat5, in diverse human tumor specimens, including myeloma, leukemia, lymphoma, melanoma and carcinomas from prostate, ovary and head and neck. Persistent Stat activity is established as essential for malignant transformation of cultured cells by many oncogenic signaling pathways. For example, the Src, Janus kinase, and epidermal growth factor receptor family tyrosine kinases are frequently activated in breast cancer cells and induce Stat3 activation. Blocking tyrosine kinase pathways with selective pharmacologic inhibitors results in decreased Stat3 activity, growth inhibition, and apoptosis. Persistent activation of Stat3 and Stat5 in tumor cells has been shown to participate in regulating expression of genes involved in controlling cell cycle progression, apoptosis, and angiogenesis. For instance, an oncogenic mutant of Stat3 induces expression of cyclin D1, Bcl-xL, and c-Myc.
Identification of molecular markers may help guide physicians in the selection of an appropriate chemotherapeutic agent. Identification of molecular markers may aid in the development of target-specific therapies and guide the utilization of such specific chemotherapies.